Transmitted imbalances without phenotypic effect; new examples detected with oligonucleotide array CGH (oaCGH). C E B O C S John CK Barber [1,2,3], Shuwen Huang [1], Viv K Maloney [1], John A Crolla [1,2,3]. [1] National Genetics Reference Laboratory (Wessex) [2] Wessex Regional Genetics Laboratory Salisbury NHS Foundation Trust, Salisbury, SP2 8BJ [3] Human Genetics Division University of Southampton University School of Medicine, Southampton Association for Clinical Cytogenetics
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Transmitted imbalances without phenotypic effect; new examples detected with oligonucleotide array CGH (oaCGH). John CK Barber [1,2,3], Shuwen Huang [1],
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Transmitted imbalances without phenotypic effect;
new examples detected with oligonucleotide array CGH (oaCGH).
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John CK Barber [1,2,3], Shuwen Huang [1], Viv K Maloney [1], John A Crolla [1,2,3].
Min 5.56 Mb deletion of 8q24.21 to 8q24.22 including 1 novel and 13 known genes
Chromosome Anomaly Collection(www.ngrl.org.uk/Wessex/collection) has one precedentascertained at prenatal diagnosis and found in thephenotypically normal mother(Batanian et al Clin Genet 2001;60:371-373).
Three 2.25 Mb duplicationof 8p23.2 (Harada N et al,“Duplication of 8p23.2:a benign cytogeneticvariant?”Am J Med Genet2002;111:285-288)
Chromosome Anomaly Collection:
46,XX,del(8)(p23.1p23.3)mat.
Composite array profileof proband, mother and brother
3,176,683
7,789,937
Ensembl v48 – gene contentWith Redon CNVs in black
Deletion min 4.61 Mb to max 5.04 Mb
CSMD1 MCPH1
Variabledefensin
and olfactory receptor cluster (REPD)
Gene desert but no
evolutionarily conservednon-coding
regions
Includes MCPH1 and interrupts the Cub and Sushi Multiple Domains 1 gene (CSMD1
OMIM 608397) between exons 23 and 27……but so do other Copy Number Variations of distal 8p – see Locus 1689 of
the Database of Genomic Variants (http://projects.tcag.ca/variation)!
Case 2: Chromosomal CNV of 8p23.1-p23.2:
Conclude: novel non-causal CNV
Case 3: Sub-telomeric CNV of 17p:
Boy of 11 referred with mild developmental delay,VSD, nasal speech, ?22q11 deletion.
Interstitial deletion of 17p13.3 identified with control probes from theMLPA sub-telomere kits P023 (GEMIN4) and P070 (RPH3AL) andconfirmed using FISH with BAC RP11-411G7
A-14-P121738116,543
A-14-P114056769,430
OaCGH mapped a 653kb interstitial deletion of 17p13.3 distal to the Miller-Dieker critical region:
Precedents: two families withaffected probands, unaffected parentsand ~ 600kb sub-telomeric deletions of 17p (Martin et al, J Med Genet2002;39:734-740).
A number of copy number variationsof this region are presentin the Database of Genomic Variants(http://projects.tcag.ca/variation/).
www.ngrl.org.uk/Wessex/subtel_collection
The Transmitted Sub-Telomeric Imbalance Collection
5. Development : mild global delay, growth delay, truncal hypotoniaDysmorphism: mild micrognathia, small mouth with downturned corners, high palate, bifid uvula and epicanthic folds; turricephaly.Skeletal: talipes of R foot at birth.Other: amputation deformities of left wrist and foot. Right single palmar crease.
mat arr cgh del(1)(q21.1q21.1)(B35:CHR1:145031367->146201576-)
6. Development: normal; possible short stature for family (9th centile).Dysmorphism: none recorded.Other: bilateral anterior sutural cataracts at birth; long-sighted even with replacement lenses.
…and novel de novo c.3125G>A (p.Cys1042Tyr) mutation affecting a conserved amino acid in the preSET domain of the EHMT1 gene
confirms diagnosis of “9q34 deletion” syndrome in the proband(Drs HG Yntema and H Scheffer, Nijmegen)
Conclude: novel 16q22.3 CNV
Case 4: CNV with causal mutation
RFWD3 and FA2Hdeleted but…
High frequency CNVs to the right inred (3), green (4), or black (6) individuals;microRNA (red) and cancer gene CNVs (black) to the left
Wong et al, Am J Hum Genet 2007;80:91-104
•The smaller the probe/target, the greater the degree of polymorphism found
11,784 copy number variants in the Database of Genomic Variants http://projects.tcag.ca/variation/ Nov 29 2008 -
•Tiling BAC array shows 3,654autosomal CNVs in 95 individualsGenomes of individuals vary by up to 9 Mb or 266 loci (Wong et al, op cit)
Copy number increases in glutamate signaling genes (GLUR7, CACNG2 and AKAP5) in patients with bipolar disorder and schizophrenia - Wilson et al, Hum Molec Genet, 15, 743-749, 2006
Predict that much of this variation will be phenotypically silent and some may be cytogenetically visible
Strong association of de novocopy number mutations with autism.Sebat et al, Science 316:445-449
Copy number variation:
Reduction in median copy number of 8p23.1 DEFB4 defensin genes from 4 to 3 confers predisposition to Chrohn’s diseaseFellermann et alAm J Hum Genet, 2006;79:439-444